GB2149662A

GB2149662A - Nifedipine composition and manufacture thereof

Info

Publication number: GB2149662A
Application number: GB08426420A
Authority: GB
Inventors: Koichi Ushimaru; Tomoaki Hamakawa; Tomio Koga
Original assignee: Nippon Shinyaku Co Ltd
Current assignee: Nippon Shinyaku Co Ltd
Priority date: 1983-11-17
Filing date: 1984-10-19
Publication date: 1985-06-19
Also published as: IT8449172A0; IT1178239B; NL8403310A; GB8426420D0; US4874774A; GB2149662B; JPS60109519A; JPH048410B2; DE3442065C2; DE3442065A1; FR2555048A1; IT8449172A1; CA1238279A; KR850003501A; SE8405731D0; SE464742B; ES537705A0; FR2555048B1; KR920001459B1; ES8600928A1

Description

1 GB 2 149 662 A- 1

SPECIFICATION Nifedipine Composition and Manufacture Thereof

The present invention relates to novel pharmaceutical composition in which nifedipine (i.e.

1,4-dihydro-2,4-dimethy]-4-(2'-nitrophenyi)-3,5-dicarbomethoxypyridine) is contained and, more particularly, it relates to a nifedipine composition which is easily absorbed and with sustaining action and 5 also relates to a nifedipine composition suitable for rectal administration.

Nifedipine exhibits coronary vasodilating action and hypotensive action and is an important compound as a pharmaceutical applied for therapy of angina pectoris and hypertension. Nifedipine is a compound hardly soluble in water. Accordingly, it is hardly absorbed when given orally in its solid state. Thus, in order to increase the absorption in digestive organs and to improve its bioavailability, various pharmaceutical 10 modifications have been carried out. Such pharmaceutical modifications may be divided into two main methods.

One of them is a method in which nifedipine is made solubilized and is disclosed in, for example, Japanese laid open patent applications 531121921, 54120127, 54/44034, 54155713,54155714,54195721, and 561115726. Another method relates to a method of dissolving or dispersing nifedipine in a carrier such as 15 polymers so that the solubility of nifedipine is increased whereupon its bioavailability is improved. Such a method is disclosed, for example, in Japanese laid open patent applications 54146837, 56168619, and 57185136.

Pharmaceutical preparations manufactured by such methods exhibit sufficient absorption and prompt effectiveness since nifedipine is promptly dissolved in digestive organs. At the same time, however, sudden 20 decrease in blood pressure sometimes happens due to rapid increase of nifedipine in blood and this causes undesired side effects such as diziness on standing up and giddiness. In addition, in such easily-absorbable preparations, there is another disadvantage that nifedipine is promptly metabolized and excreted whereupon its blood level rapidly decreases and short-acting.

Thus, when such preparations are given before going bed, prevention of anginal pectoris during 25 sleeping time cannot be guaranteed and, accordingly, long-acting preparations have been waited.

Furthermore, there are several reports in which nifedipine preparations for oral use exhibit side effects on digestive organs. At present, there is no other preparations than oral ones in the market and there is another disadvantage that patients who are not in a position to swallow due to serious illness are out of the therapy by nifedipine. Anyway, parenteral preparations of nifedipine have been waited for long time. 30 Under such circumstances, the present inventors have conducted extensive studies in order to offer new nifedipine preparations in which nifedipine is easily absorbed, its blood level sufficient for the therapy can be maintained for a long period and non-oral administration is possible and, as a result, the present inventors have found that a composition in which nifedipine is contained in a base comprising a definite mixing ratio of polyalkyleneglycol and fat and oil well meetwith the requirement and the present invention 35 has been achieved.

Thus, the present invention relates to a nifedipine composition with desired absorbability and long-acting action, characterized in that, nifedipine is contained in a base comprising 5 to 50 parts by weight of polyalkyleneglycol and 50 to 95 parts by weight of fat and oil.

Examples of polyalkyleneglycols applicable in the present invention are polyethyleneglycol and polypropyieneglycol and polyethyleneglycol with a molecular weight range of 200 to 20,000 is most preferred. Examples of fat and oil applicable in the present invention are fatty acid glycerides and, more particularly, fatty acid glycerides with 12 to 18 carbon atoms. Preferred examples of such glycerides are Adeps Solidus (German Pharmacopeia) and preparations corresponding to it such as, for example, Witepsol (Registered Trademark) (Dynamit-Novel Company) of types H, W, Sand E. Besides them, cacao 45 butter and other vegetable fats and oils and hardened oils thereof are also applicable.

In the present invention, the mixing ratio of polyalkyleneglycol and fat and oil is very important and preparations with sufficient absorption and sustaining action are obtained only when nifedipine is contained in a base comprising 5 to 50 parts by weight of polyalkyleneglycol and 50 to 95 parts by weight of fatandoil.

In the above-given mixed base, nifedipine is contained at about 0.1 to 5% and, preferably, 0.25 to 2% concentration. It is of course possible that the present invention composition may also contain other substances such as nonionic su rfactants finely powdered silicic acid compounds and cellulose derivatives.

The present invention composition is prepared as follows. Thus, nifedipine is dissolved in polyalkyieneglycol and then mixed with warm and melted fat and oil or nifedipine is added to and dissolved 55 in a warm and melted mixture of polyalkyleneglycol and fat and oil. Then the mixture is poured into a mold or container for suppositories and allowed to cooled. Since nifedipine is unstable to light, it is desired to conduct the above operation in dark place. The present invention composition is used by parenteral route and it is most desired to give by rectal route.

The present invention will now be more concretely illustrated by way of representative examples. 60 EXAMPLE 1

To 21 grams of polyethyleneglyocol (400) was added 1 gram of nifedipine and the mixture was stirred and made dissolved. Then 84 grams of Witepsol H-1 5 melted at 4WC was added thereto, the mixture was 2 GB 2 149 662 A 2 stirred, poured into a mold for suppositories (for 2 gram preparations) (Erweka Co) and allowed to cooled to give nifedipine suppositories for rectal administration.

EXAMPLE 2

A mixture of 73.5 grams of Witepsol W-35 and 32 grams of polyethyleneglycol (1500) was melted at 50'C, 0.5 gram of nifedipine was added thereto, the mixture was stirred and made dissolved, and treated the 5 same as in Example 1 to give nifedipine suppositories.

EXAMPLE 3

Polyethyleneglycol (1500) (42 grams) was melted at 50C and 1 gram of nifedipine was dissolved therein. Then 63 grams of Witepsol S-55 melted at 50"C was added thereto, the mixture was stirred and treated the same as in Example 1 to give nifeclipine suppositories.

EXAMPLE 4

Polyethyleneglycol (1500) (31.5 grams) was melted at WC and 1 gram of nifedipine was dissolved therein. Then 73.5 grams of Witepsol S-55 melted at WC was added thereto, the mixture was stirred and treated the same as in Example 1 to give nifedipine suppositories.

EXAMPLE 5

Polyethyleneglycol (1500) (21 grams) was melted at 50'C and 1 gram of nifedipine was added thereto to dissolve therein. Then 84 grams of Witepsol S-55 melted at 50'C was added thereto, the mixture was stirred and treated the same as in Example 1 to give nifedipine suppositories.

EXAMPLE 6

Witepsol W-35 (52.5 grams) and 52.5 grams of polyethyleneglycol (1540) were melted at WC, 1 gram of 20 nifedipine was added thereto, the mixture was stirred to make dissolved, and treated the same as in Example 1 to give nifedipine suppositories.

EXAMPLE7

Polyethyleneglycol (1500) (26.25 grams) was melted at 50'C and 2 grams of nifedipine was dissolved therein. Then 78.75 grams of Witepsol S-55 melted at 500C was added thereto, the mixture was stirred, and 25 treated the same as in Example 1 give nifedipine suppositories.

EXAMPLE 8

Polyethyleneglycol (1000) (42 grams) was melted at 50C and 1 gram of nifedipine was added thereto and dissolved therein after stirring. Then 63 grams of cacao butter melted at 50'C was added thereto, the mixture was stirred and treated the same as in Example 1 to give nifedipine suppositories.

Effect of the present invention will be explained as follows.

Suppositories (20 mg nifedipine/2 grams) prepared by dissolving nifedipine in a base comprising polyethyleneglycols (PEG-400: PEG-1 500: PEG-600=3:3:4), those (20 mg nifedipine/2 grams) prepared by dispersing nifedipine in Witepsol S-55 base, and those prepared in accordance with Examples 3,4 and 5 each were given to beagles (10 to 11 kg body weight) (four dogs per one group) at the dose of 2 mg/kg from 35 rectal route, blood was collected from time to time, and the nifedipine concentrations in blood serum were determined. Method of determination is as follows. Thus, to the collected blood serum was added n-propyl p-hydroxybenzoate as an internal standard, then trichloroacetic acid was added thereto to remove proteins, centrifuged, the supernatant liquid was extracted with ethyl acetate, and determined by high performance liquid chromatography. The result is given in Fig. 1.

Also, an area under blood serum level curve for each preparation until eight hours after administration was measured and the area (AUC) was compared with another AUC when 2 mg/kg of injection solution (prepared by dissolving nifedipine in 50% aqueous polyethyleneglycol solution) was administered intravenously and the ratio was calculated. The result is given in Table 1.

TABLE 1 45

Ratio of areas under blood serum level curve Suppositories prepared from PEG base Suppositories prepared from Witepsoi S-55 13.1 9.3 Suppositories of Example 3 Suppositories of Example 4 Suppositories of Example 5 the case of intravenous injection was set 100.

31.0 26.6 23.9 3 GB 2 149 662 A 3 Out of results given in Fig. 1 and Table 1, it is quite apparent that the nifedipine preparations according to the present invention exhibit high blood serum level for a long time as compared with the preparations prepared only from polyethyleneglycol or Witepsol base. Also, with reference to bioavailability, the present invention preparations are twice or thrice as stronger as the preparations for comparison. Anyway, marked 5 effect of the present invention is quite obvious.

Brief Explanation of Drawing Fig. 1 shows mean values of nifedipine level in blood serum when the following nifedipine suppositories are given at the dose of 2 mglkg to rectum of beagles (body weight: 10 to 11 kg) (one group consists of four dogs). Ordinate and abscissa show blood serum level (ng/mi) and time elapsed (hours), 10 respectively.

0-0 Suppository prepared from polyethyleneglycol only A-A Suppository prepared from Witepsol S-55 base only Suppository prepared according to Example 3 Suppository prepared according to Example 4 A-A Suppository prepared according to Example 5 15

Claims

1. Nifedipine composition particularly suitable for rectal administration, characterized in that, nifedipine is contained in a base comprising 5 to 50 parts by weight of polyalkyleneglycol and 95 to 50 parts by weight of fat and oil.

2. The composition according to Claim 1 in which the molecular weight in average of the said 20 polyalkylenegiycol is 200 to 20,000.

3. The composition according to Claim 1 or 2 in which the said fat and oil is fatty acid glyceride.

4. A method of manufacturing nifeclipine preparation particularly suitable for rectal administration in which Nifedipine is contained in a base comprising 5 to 50 parts by weight of polyalkyleneglycol and 95 to 50 parts by weight of fat and oil, characterized in that, nifedipine is dissolved in polyalkyleneglycol, then 25 warm and melted fat and oil are added thereto, and the mixture is homogeneously mixed or nifedipine is added to and mixed with a warm and melted mixture of polyalkyleneglycol and fat and oil, then the resulting homogeneous mixture is poured into suitable mold or the like such as a cast or a container and finally cooled.

Printed for Her Majesty's Stationery Office by Courier Press, Leamington Spa. 611985. Demand No. 8817443.

Published by the Patent Office, 25 Southampton Buildings, London, WC2A JAY, from which copies may be obtained.